Ion channel modulators

Abstract

The invention relates to compounds, compositions comprising the compounds, and methods of using the compounds and compound compositions. The compounds, compositions, and methods described herein can be used for the therapeutic modulation of ion channel function, and treatment of disease and disease symptoms, particularly those mediated by certain calcium channel subtype targets.

1 . A compound of formula (I) or pharmaceutical salt thereof  
       
         
           
           
               
               
           
         
         wherein,  
         Ar 1  is cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substitutents;  
         X is NR 3 , C(R 3 ) 2 , or O;  
         Y is C═O or lower alkyl;  
         R 1  is Ar 2  or lower alkyl optionally substituted with Ar 2 ;  
         each Ar 2  is independently cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substitutents;  
         q is 0, 1 or 2;  
         each R 2  is independently selected from (CH 2 ) m CO 2 R 3 , (CH 2 ) m COAr 3 , (CH 2 ) m CONR 3 R 4 , (CH 2 ) m Ar 3 , (CH 2 ) 3 Ar 3 , (CH 2 ) n NR 3 R 4  or (CH 2 ) n OR 4 ;  
         each R 3  is independently selected from H, or lower alkyl;  
         each R 4  is independently selected from H, lower alkyl or (CH 2 ) p Ar 3 ;  
         m is 1 or 2;  
         n is 2 or 3;  
         p is 0 or 1;  
         each Ar 3  is cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substitutents;  
         each substitutent for Ar 1 , Ar 2  and Ar 3  is independently selected from halogen, CN, NO 2 , OR 5 , SR 5 , S(O) 2 OR 5 , NR 5 R 6 , cycloalkyl, C 1 -C 2  perfluoroalkyl, C 1 -C 2  perfluoroalkoxy, 1,2-methylenedioxy, C(O)OR 5 , C(O)NR 5 R 6 , OC(O)NR 5 R 6 , NR 5 C(O)NR 5 R 6 , C(NR 6 )NR 5 R 6 , NR 5 C(NR 6 )NR 5 R 6 , S(O) 2 NR 5 R 6 , R 7 , C(O)R 7 , NR 5 C(O)R 7 , S(O)R 7 , or S(O) 2 R 7 ;  
         each R 5  is independently selected from hydrogen or lower alkyl optionally substituted with one or more substitutent independently selected from halogen, OH, C 1 -C 4  alkoxy, NH 2 , C 1 -C 4  alkylamino, C 1 -C 4  dialkylamino or C 3 -C 6  cycloalkyl;  
         each R 6  is independently selected from hydrogen, (CH 2 ) p Ar 4 , or lower alkyl optionally substituted with one or more substitutent independently selected from halogen, OH, C 1 -C 4  alkoxy, NH 2 , C 1 -C 4  alkylamino, C 1 -C 4  dialkylamino or C 3 -C 6  cycloalkyl;  
         each R 7  is independently selected from (CH 2 ) p Ar 4  or lower alkyl optionally substituted with one or more substitutent independently selected from halogen, OH, C 1 -C 4  alkoxy, NH 2 , C 1 -C 4  alkylamino, C 1 -C 4  dialkylamino or C 3 -C 6  cycloalkyl; and  
         each Ar 4  is independently selected from C 3 -C 6  cycloalkyl, aryl or heteroaryl, each optionally substituted with one to three substitutents independently selected from halogen, OH, C 1 -C 4  alkoxy, NH 2 , C 1 -C 4  alkylamino, C 1 -C 4  dialkylamino or 1,2-methylenedioxy.  
       
     
     
         2 . The compound of  claim 1 , wherein Ar 1  is aryl or heteroaryl, each optionally substituted with one or more substitutents; X is NR 3 ; and Y is C═O.  
     
     
         3 . The compound of  claim 1 , wherein R 1  is aryl or heteroaryl, each optionally substituted with one or more substitutents.  
     
     
         4 . The compound of  claim 1 , wherein each R 2  is independently (CH 2 ) m Ar 3 ; and each Ar 3  is heteroaryl optionally substituted with one or more substitutents.  
     
     
         5 . The compound of  claim 1 , wherein Ar 3  is a heteroaryl comprising a five-membered ring having carbon atoms and 1, 2 or 3 heteroatoms selected from N, O and S, optionally substituted with one or more substitutents.  
     
     
         6 . The compound of  claim 1 , wherein Ar 3  is pyrrolidinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, benzimidazolyl, benzoxazolyl, or benzthiazolyl, each optionally substituted with one or more substitutents.  
     
     
         7 . The compound of  claim 1 , wherein each R 2  is, (CH 2 ) n NR 3 R 4 , wherein each R 4  is independently (CH 2 ) p Ar 3 .  
     
     
         8 . The compound of  claim 7 , wherein R 3  is H.  
     
     
         9 . The compound of  claim 1 , wherein the compound of formula I is a compound delineated in any of Table 1, or pharmaceutical salt thereof.  
     
     
         10 . A method of treating a disease or disease symptom in a subject in need thereof comprising administering to the subject an effective amount of a compound of formula (I), or pharmaceutical salt thereof, according to  claim 1 .  
     
     
         11 . The method of  claim 10 , wherein the disease or disease symptom is modulated by calcium channel Ca v 2.  
     
     
         12 . The method of  claim 11 , wherein the disease or disease symptom is modulated by calcium channel Ca v 2.2.  
     
     
         13 . The method of  claim 10 , wherein the disease or disease symptom is angina, hypertension, congestive heart failure, myocardial ischemia, arrhythmia, diabetes, urinary incontinence, stroke, pain, traumatic brain injury, or a neuronal disorder.  
     
     
         14 . A method of modulating calcium channel activity comprising contacting a calcium channel with a compound of formula I in  claim 1 .  
     
     
         15 . A method of making a compound of formula I in  claim 1 , comprising reacting an intermediate delineated herein with a reagent to provide a compound of formula I as defined herein.  
     
     
         16 . A composition comprising a compound of formula I, or pharmaceutically acceptable salt thereof, according to  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         17 . The composition of  claim 16 , further comprising an additional therapeutic agent.  
     
     
         18 . A method of modulating Ca v 2 activity in a subject in need thereof comprising administering to the subject an effective amount of a compound of formula (I) in  claim 1 , or pharmaceutical salt thereof.